1. Field of the Invention
The present invention relates to the field of treating chronic inflammatory diseases.
2. Background of the Invention
T regulatory cells, or T reg cells, are a subclass of T cells, capable of inhibiting Th1- and Th2-driven inflammatory responses that contribute to the development of autoimmune diseases, such as, type I diabetes, multiple sclerosis, inflammatory bowel disease, and atherosclerosis, among others. Of particular interest is the identification of novel molecular mechanisms underlying the development and suppression function of T regs as a means for establishing new strategies for treating autoimmune diseases.
With respect to atherosclerosis, atherogenesis is the developmental process that results in the formation of atheromatous plaques, which may lead to atherosclerosis. T cell activation plays an important role in atherogenesis (e.g., by macrophage activation/recruitment; SMC proliferation; and collagen formation). For example, it has been shown that injection of Tr1 T regulatory cells—a subset of T regs that have been previously identified, along with natural regulatory CD4+CD25+ cells and Th3 cells—was able to decrease atheroma size in ApoE−/−mice (Mallat Z. et al., 2003). In addition, injection of CD4+CD25+ T regulatory cells was able to reduce lesion size in mouse models of atherosclerosis. The same study also showed that a depletion of T regulatory cells accelerated atherosclerosis in mice (Ait-Oufella et al., 2006). Thus studies have shown an important role for T reg cells in inhibiting the progression of atherosclerosis in mice.
It has been previously shown that TGF-β1 (transforming growth factor β1) may play a role in regulating the activity of T reg cells. TGF-β1 is a pleiotropic growth factor important in cell growth, differentiation, and activation in a number of immune and non-immune cell types (Feinberg and Jain, 2005; Li and Flavell, 2008; Shi et al., 1999). TGF-β1 is involved in the maintenance of self-tolerance and homeostasis of several T cell effectors including T regulatory cells (Fantini et al., 2004; Li et al., 2006; Wan and Flavell, 2005). Indeed, disruption of TGF-β1 or its receptors in T cells induces a severe lymphoproliferative response and autoimmunity (Marie et al., 2006; Shull et al., 1992). Thus, tight control of TGF-β1 and its downstream signaling pathways may allow for fine-tuning of the immune response by modulating T regulatory cell development or function. With particular regard to atherosclerosis, the effect of T regulatory cells in limiting atherosclerosis has been shown to be dependent in part on TGF-β signaling. TGF-β has potent immunosuppressive effects on multiple cell types, including effects on T cell activation, SMC proliferation, collagen formation, endothelial proliferation, and macrophage activation.
Additionally, with regard to CD4+CD25+ T reg cells, TGF-β1 signaling is believed to be required for the differentiation of CD4+CD5− T reg cells to CD4+CD5+ T reg cells. TGF-β is also required for peripheral maintenance of CD4+CD25+ cells and their suppression function, but not for their thymic development (Marie et al., 2005). The suppression function of CD4+CD25+ cells includes inhibition of the inflammation response, e.g., due to the immune response to intracellular pathogens. Because inflammation is also associated with pathologies such as atherosclerosis, type I diabetes, and multiple sclerosis, TGF-β1 signaling may inhibit atherosclerosis by conferring T regulatory function and control of inflammation.
An additional possible regulator of T reg cells are the Kruppel-like family of proteins, or KLFs, which a family of related zinc-finger transcription factors that have roles in various aspects of cellular growth, development and differentiation, particularly in the hematopoietic system. Several KLFs with these properties have been identified, including KLFs 1-4. KLF1, or EKLF has been shown to be essential for erythropoiesis. KLF2, or LKLF (KLF2) plays a role in T-lymphocyte development. KLF3, or BKLF, has been implicated in the of myeloproliferative disorder. KLF4 or GKLF, is involved in epithelial development, including differentiation of gut, skin, monocyte. Because of the importance of KLFs in different hematopoietic lineages, Kruppel-like zinc-finger protein may regulate the differentiation or function of T reg cells.
Due to the wide prevalence of autoimmune diseases, including type I diabetes, multiple sclerosis, inflammatory bowel disease, and atherosclerosis, among others, as well as the limited treatment options that are available, there remains a need for new strategies for developing and obtaining useful therapeutics for combating these disorders.